The management of chronic wounds, including bed sores in the elderly, remains a huge unmet medical need. Palmitoylethanolamide (PEA) is an endogenous lipid-derived agonist of the nuclear receptor, PPAR- (peroxisome-proliferator-activate receptor-), which is thought to play important roles in the regulation of inflammation and skin repair. Tissue PEA levels are substantially decreased in patients suffering from rheumatoid arthritis or osteoarthritis. Moreover, pro-inflammatory stimuli suppress PEA production in innate immune cells from rats and mice, suggesting that endogenous PEA might serve as a stop signal for inflammation. The biological actions of PEA are terminated by the enzyme N-acylethanolamine-hydrolyzing acid amidase (NAAA), which is highly expressed in macrophages. To explore the role of PEA in the regulation of inflammatory pain, the lab of Daniele Piomelli at the University of California, Irvine, has developed the first class of potent NAAA inhibitors and showed that these compounds increase PEA levels and reduce inflammatory responses in vitro and in vivo. A new member of this class, called ARN077, was recently shown to suppress inflammatory responses in the skin and accelerate wound healing in mice. These results support the hypothesis that NAAA inhibitors such as ARN077 might offer an innovative target to treat bed sores and other chronic wounds. Our application has two primary goals aimed at testing this hypothesis: (1) Characterize the effects of ARN077 in preclinical models of wound healing. We will characterize, both at histological and biochemical level, the effects of ARN077 in a mouse model of open wound healing and a rat model of pressure-induced skin ulcers. (2) Evaluate the pharmacokinetic and safety profile of ARN077. Preliminary experiments have shown that ARN077 is chemically stable in FDA-approved topical formulations and highly effective when administered as a topical drug, but is rapidly hydrolyzed in plasma. We will use liquid chromatography/mass spectrometry to determine the pharmacokinetic profile of ARN077 following acute or prolonged topical administration in mice. In addition, we will test whether prolonged treatment with ARN077 might cause irritation or other pathological alterations of the skin (e.g., atrophy). If the results of the studies outlined above support our hypothesis, we will apply for SBIR Phase 2 funding to continue the preclinical development of ARN077. PUBLIC HEALTH RELEVANCE: Current medicines do not adequately treat pressure ulcers (also called 'bed sores'), a common ailment associated with prolonged confinement to a bed. We recently discovered a new class of compounds that alleviate inflammation and accelerate wound healing in animals by targeting a newly identified enzyme called N-Acylethanolamide-hydrolyzing Acid Amidase (NAAA). Here, we propose to lay the groundwork needed to translate this research finding into a clinically useful treatment for bed sores in the elderly.